TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

Zhao, Limin; Hao, Ke; Xu, Haibo; Wang, Guo Dong; Zhang, Honglei; Zou, Li; Xiang, Sheng; Li, Mengyuan; Li, Peng; Zhou, Mingfang; Ao, Lei; Yang, Qin; Shen, Che Kun James; Yi, Ping; Wang, Lu; Jiao, Baowei

doi:10.1038/s41467-019-14183-1

Cited by 28 publications

(26 citation statements)

References 67 publications

(88 reference statements)

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“…In agreement with this model, analysis of a conditional knockout of Xdh has shown that Xdh is required to recruit Btn1a1 into the docking complex and that in the absence of Xdh large LDs accumulate in a similar manner to the Btn1a1 null mouse 15 . Such functional Btn1a1‐Xdh interactions are also compatible with additional mutant mouse lines impacting either Btn1a1 and/or Xdh expression during lactation 16–18 …”

Section: Introductionsupporting

confidence: 53%

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The butyrophilin 1a1 knockout mouse revisited: Ablation ofBtn1a1leads to concurrent cell death and renewal in the mammary epithelium during lactation

et al. 2021

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Butyrophilin 1A1 (BTN1A1) is implicated in the secretion of lipid droplets from mammary epithelial cells as a membrane receptor, which forms a secretion complex with the redox enzyme, xanthine oxidoreductase (XDH). The first evidence that BTN1A1 functions in this process was the generation of Btn1a1−/− mouse lines, in which lipid secretion was disrupted and large unstable droplets were released into alveolar spaces with fragmented surface membranes. We have revisited one of these mutant mouse lines using RNAseq and proteomic analysis to assess the consequences of ablating the Btn1a1 gene on the expression of other genes and proteins. Disruption of intact Btn1a1 protein expression led to a large build‐up of Xdh in the cytoplasm, induction of acute phase response genes and Lif‐activation of Stat3 phosphorylation. At peak lactation, approx. 10% of the cells were dying, as assessed by TUNEL‐analysis of nuclear DNA. Possible cell death pathways included expression of caspase 8 and activated caspase 3, autophagy, Slc5a8‐mediated inactivation of survivin (Birc5), and pStat3‐mediated lysosomal lysis, the latter of which is the principal death route in involuting wild type cells. Milk secretion was prolonged by renewal of the secretory epithelium, as evidenced by the upregulation of Ki67 in approx. 10% of cell nuclei and expression of cyclins and Fos/Jun. These data highlight the plasticity of the mammary epithelium and the importance of functional BTN1A1 expression for maintenance of terminally differentiated secretory cells and optimal milk production throughout lactation.

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Section: Introductionsupporting

confidence: 53%

“… 15 Such functional Btn1a1‐Xdh interactions are also compatible with additional mutant mouse lines impacting either Btn1a1 and/or Xdh expression during lactation. 16 , 17 , 18 …”

Section: Introductionmentioning

confidence: 99%

The butyrophilin 1a1 knockout mouse revisited: Ablation ofBtn1a1leads to concurrent cell death and renewal in the mammary epithelium during lactation

et al. 2021

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“…Comparison of the two sets of results yields an R 2 value of 0.99 with a slope of 1.13 ( Figure 5B ). All the antibodies we used here are well-validated and widely applied in the previous studies (Maugeri et al, 2014 ; Pellegrini et al, 2018 ; Chen et al, 2019 ; Jia et al, 2019 ; Dubois et al, 2020 ; Harish et al, 2020 ; Li et al, 2020 ; Lin et al, 2020 ; Watson et al, 2020 ; Zhao et al, 2020 ). The staining patterns we obtained are also consistent with the ones generated by antibodies from different clones (Uhlén et al, 2015 ; Thul et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Highly Sensitive and Multiplexed Protein Imaging With Cleavable Fluorescent Tyramide Reveals Human Neuronal Heterogeneity

Liao

Mondal

Nazaroff

et al. 2021

Front. Cell Dev. Biol.

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The ability to comprehensively profile proteins in intact tissues in situ is crucial for our understanding of health and disease. However, the existing methods suffer from low sensitivity and limited sample throughput. To address these issues, here we present a highly sensitive and multiplexed in situ protein analysis approach using cleavable fluorescent tyramide and off-the-shelf antibodies. Compared with the current methods, this approach enhances the detection sensitivity and reduces the imaging time by 1–2 orders of magnitude, and can potentially detect hundreds of proteins in intact tissues at the optical resolution. Applying this approach, we studied protein expression heterogeneity in a population of genetically identical cells, and performed protein expression correlation analysis to identify co-regulated proteins. We also profiled >6,000 neurons in a human formalin-fixed paraffin-embedded (FFPE) hippocampus tissue. By partitioning these neurons into varied cell clusters based on their multiplexed protein expression profiles, we observed different sub-regions of the hippocampus consist of neurons from distinct clusters.

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“…To evaluate whether PTA and TCEP can cleave the fluorophore and deactivate HRP simultaneously, we stained HMGB1, HDAC2, TAP43, PABPN1, hnRNP A1, Nucleolin, H4K16ac, hnRNP K, ILF3 and Nucleophosmin with HRP labeled antibodies and the high-performance tyramide-N 3 -Cy5 in HeLa cells ( Figure 4 ). All the antibodies used in this study are well-validated and documented in the literature [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. With the PTA and TCEP treatment, over 95% of the staining signals were erased, leading to the on/off ratio of about 20:1.…”

Section: Resultsmentioning

confidence: 99%

Multiplexed In Situ Protein Profiling with High-Performance Cleavable Fluorescent Tyramide

et al. 2021

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Understanding the composition, function and regulation of complex cellular systems requires tools that quantify the expression of multiple proteins at their native cellular context. Here, we report a highly sensitive and accurate protein in situ profiling approach using off-the-shelf antibodies and cleavable fluorescent tyramide (CFT). In each cycle of this method, protein targets are stained with horseradish peroxidase (HRP) conjugated antibodies and CFT. Subsequently, the fluorophores are efficiently cleaved by mild chemical reagents, which simultaneously deactivate HRP. Through reiterative cycles of protein staining, fluorescence imaging, fluorophore cleavage, and HRP deactivation, multiplexed protein quantification in single cells in situ can be achieved. We designed and synthesized the high-performance CFT, and demonstrated that over 95% of the staining signals can be erased by mild chemical reagents while preserving the integrity of the epitopes on protein targets. Applying this method, we explored the protein expression heterogeneity and correlation in a group of genetically identical cells. With the high signal removal efficiency, this approach also enables us to accurately profile proteins in formalin-fixed paraffin-embedded (FFPE) tissues in the order of low to high and also high to low expression levels.

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TDP-43 facilitates milk lipid secretion by post-transcriptional regulation of Btn1a1 and Xdh

Cited by 28 publications

References 67 publications

The butyrophilin 1a1 knockout mouse revisited: Ablation ofBtn1a1leads to concurrent cell death and renewal in the mammary epithelium during lactation

The butyrophilin 1a1 knockout mouse revisited: Ablation ofBtn1a1leads to concurrent cell death and renewal in the mammary epithelium during lactation

Highly Sensitive and Multiplexed Protein Imaging With Cleavable Fluorescent Tyramide Reveals Human Neuronal Heterogeneity

Multiplexed In Situ Protein Profiling with High-Performance Cleavable Fluorescent Tyramide

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